Brief Summary Changes in the synaptic efficacy of excitatory and inhibitory transmission can perturb the delicate balance of excitation and inhibition within the brain and thus profoundly modulate cognitive processes. The overall goal of this research proposal is to understand the mechanisms by which TRPV1, a non-selective cation channel, may be involved in the modulation of synaptic efficacy at both excitatory and inhibitory synapses in the hippocampus and dentate gyrus, two key brain areas involved in learning and memory formation and where TRPV1 is highly expressed. TRPV1 is generally thought to be expressed presynaptically, and might retrogradely be activated by different lipid ligands including endocannabinoids (eCBs). The experiments proposed here are designed to test the possibility that TRPV1 may act postsynaptically to reduce the number or responsiveness of glutamate and GABA receptors. In addition, I will test the possibility that eCBs, which typically signal in a retrograde manner by activating presynaptic cannabinoid receptors, could also act in an autocrine manner to regulate postsynaptic receptor function via TRPV1. First, I will analyze the cellular and molecular mechanism underlying TRPV1 activation as well as the mechanism downstream by which TRPV1-mediated physiological effect at CNS synapses. Second, I will expand our analyses to understand the contribution of several G-protein coupled receptors in regulating TRPV1- mediated changes of synaptic efficacy. This information is essential to gain a better understanding on the role of brain TRPV1 in regulating synaptic and neural circuit function. PUBLIC HEALTH RELEVANCE: TRPV1 channels have recently become an attractive molecular target for the development of new drugs to control pain in the peripheral nervous system. Undesirable side-effects may arise from unknown and previously unexplored TRPV1 functions in the central nervous system. Unmasking the role of TRPV1 in the central nervous system is not only relevant to the development of novel analgesic strategies but it may also provide new insights into the cellular basis underlying brain function under normal and pathophysiological conditions.